Devices for creating vascular grafts by vessel distension using rotatable elements

ABSTRACT

Devices and methods are provided for forming a vascular graft by axially distending a blood vessel to induce growth. The device preferably comprises a stretching mechanism which includes (i) a stabilization rod, (ii) a pair of rotatable elements, wherein each rotatable element is rotatably attached to the elongated body and has a channel substantially perpendicular to the axis of rotation, and (iii) a means for rotating each rotatable element to axially distend a blood vessel positioned in the channels of the rotatable elements. The elements can be rotated intermittently, cyclically, or continuously, over a period to distend or elongate the donor vessel. Preferably, the device is implanted, for example using endoscopic techniques, for use in vivo, although the device also can be used in vitro.

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority is claimed to U.S. provisional application No. 60/274,702,filed Mar. 9, 2001, and to U.S. application Ser. No. 09/322,095, filedMay 28, 1999, now U.S. Pat. No. 6,322,553, which claims priority to U.S.provisional application Serial No. 60/087,027, filed May 28, 1998, allof which are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

The present invention is generally in the area of methods and devices toobtain vascular tissue grafts and more specifically in the area ofmethods and devices to obtain grafts, preferably autologous grafts,prepared from living vascular tissue.

Vascular grafts are commonly used by surgeons to bypass obstructions toblood flow caused by the presence of atherosclerotic plaques. Vasculargrafts also are used in other applications such as providingarterial-venous shunts in dialysis patients, vascular repair orreplacement and treating aneurysms. Grafts for bypass are often, but notexclusively, used in the coronary arteries, the arteries that supplyblood to the heart. The materials used to construct a vascular graftusually are either synthetic or of biological origin, but combinationsof synthetic and biological materials are under development. The mostwidely used biological vascular grafts are autologous saphenous vein ormammary artery. Some common synthetic grafts are made ofpolytetrafluoroethylene (PTFE) (e.g., GORTEX™) or polyester (e.g.,DACRON™). Autologous grafts have generally been used more successfullythan synthetic grafts. Autologous grafts remain patent (functional) muchlonger than synthetic grafts, and saphenous veins often fail in lessthan five years. The short lifetime of synthetic grafts is especiallyevident with small diameter (less than 7 mm diameter) grafts, as mostsmall diameter synthetic grafts occlude within one to two years or less.

Small diameter vascular grafts are particularly used in coronary arterybypass surgery. Internal mammary artery (IMA) is the autologous graft ofchoice, because it typically has a longer life than venous grafts (95%patent at 5 years versus 85% patent at 2 years). Mammary arterialtissue, however, is difficult to harvest, typically is not available inlengths sufficient for multiple bypasses, and its removal can result inproblems such as problematic wound healing. Moreover, obtainingsufficient venous tissue for repairing an occluded artery can beproblematic in patients with venous conditions such as varicose veinsand especially in second or third surgeries in the same patient. Recentliterature also suggests that IMA used in bypass procedures either failssoon after transplantation or remains patent indefinitely. See, e.g.,Bergsma, et al., Circulation 97(24):2402-05 (1998); Cooley, Circulation97(24):2384-85 (1998). Other arteries such as the gastroepipolic,gastric, radial, and splenic also are used in coronary bypassprocedures. Moreover, the recent American Heart Association/AmericanCollege of Cardiology consensus document (Eagle, K. A., et al. “ACC/AHAGuidelines for coronary artery bypass graft surgery: A report of theAmerican College of Cardiology/American Heart Association Task Force onPractice Guidelines”, Committee to Revise the 1991 Guidelines forCoronary Artery Bypass Graft Surgery, American College ofCardiology/American Heart Association, J. Am. Coll. Cardiol.,34(4):1262-347 (1999)) strongly recommends a move to total arterialrevascularization.

In some cases, autologous or homologous saphenous vein preserved byfreezing or other processes is used.

With people living longer, multiple surgeries are more common. At thesame time, open-heart surgery is becoming routine, aided by thedevelopment of new, minimally invasive and “off-pump” procedures thathave dramatically simplified the surgery and reduced the recovery time.

Development of a longer lasting small-diameter vascular graft is thesubject of much academic and industrial research. One current approachis to combine cell culture and biomaterials technologies to make aliving, “tissue engineered” graft. This effort, however, is hindered bythe requirements of a successful graft: It should be self-repairing,non-immunogenic, non-toxic, and non-thrombogenic. The graft also shouldhave a compliance comparable to the artery being repaired, be easilysutured by a surgeon, and not require any special techniques or handlingprocedures. Grafts having these characteristics are difficult toachieve. Despite the substantial effort to date and the potential forsignificant financial reward, academic and industrial investigators havefailed to produce graft materials that have demonstrated efficacy inhuman testing.

Efforts to avoid or minimize the need for vascular grafts for repair ofotherwise healthy vascular tissue have been described. For example,Ruiz-Razura et al., J. Reconstructive Microsurgery, 10(6):367-373 (1994)and Stark et al., Plastic & Reconstructive Surgery, 80(4):570-578 (1987)disclose the use of a round microvascular tissue expander for acutearterial elongation to examine the effects on the tissue of such acutehyperextension. The expander is a silicone balloon that is placed underthe vessel to be elongated. The balloon is filled with saline over avery short period, causing acute stretching and elongation of thevessel. The method is purported to be effective for closure of arterialdefects up to 30 mm without the need for a vein graft. These techniquesare appropriate for trauma, but are not used for restoring blood flow invessels that are occluded, for example by disease, which are treated bysurgically bypassing the obstruction with a graft. The disclosed methodsand devices fail to provide an autologous graft or versatile substitute.Moreover, the acute stretching may damage the vessel.

It is therefore an object of the present invention to provide devicesand methods for creating natural blood vessel suitable for grafting.

It is another object of the present invention to provide devices andmethods for making an autologous blood vessel graft.

It is further object of the present invention to provide devices andmethods for creating blood vessel grafts in vivo or in vitro.

These and other objects, features, and advantages of the presentinvention will become apparent upon review of the following detaileddescription of the invention taken in conjunction with the drawings andthe appended claims.

SUMMARY OF THE INVENTION

Devices and methods are provided for forming a vascular graft by axiallydistending a blood vessel to stimulate vessel growth. Preferably, thedevice is implanted, for example using endoscopic techniques, for use invivo. A portion of a blood vessel (i.e. the donor vessel) then isdistended using the device. Preferred donor vessels include thegastroepipolic artery, as well as the internal mammary, femoral,gastric, splenic, and radial arteries. Then, the in vivo distendedportion of the donor vessel is excised, for example, at the time ofbypass surgery. In an alternative embodiment, a section of donor vesselis surgically excised from the bypass surgery patient, preferably at thetime of by-pass surgery, and then distended in vitro in a medium forcell growth, e.g., in an organ culture system or bioreactor. Where thedonor is the recipient of the graft, the result using either approachadvantageously is a totally autologous, living vascular graft.

In a preferred embodiment, the device comprises a stretching mechanismwhich includes (i) a stabilization rod, (ii) a pair of rotatableelements, wherein each rotatable element is rotatably attached to theelongated body and has a channel substantially perpendicular to the axisof rotation, and (iii) a means for rotating each rotatable element toaxially distend a blood vessel positioned in the channels of therotatable elements. The elements can be rotated intermittently,cyclically, or continuously, over a period to distend or elongate thedonor vessel.

The rotatable elements can, in one embodiment, comprise a pair of armsextending from a central base, the arms being capable of bending orflexing between a straight configuration and a curved configuration. Thestraight configuration preferably is used to give the device a narrowprofile suitable for endoscopic insertion into a donor patient. The armscan have an inherent spring action, such that the relaxed state of thearms is a curved configuration and wherein the arms will transform fromthe straight configuration into a curved configuration upon release ofone or more releasable fasteners.

In another variation, the rotatable elements each comprise a pair ofrounded lobes extending from a central base, the channel extendingbetween each pair of lobes. The lobes can comprise a disk-shaped portionhaving an outer edge surface distal the axis of rotation of therotatable element and a substantially flat upper surface distal thestabilization rod. The outer edge surface can include one or moregrooves in which a blood vessel or portion thereof can be positioned,supported and guided during the stretching process.

The means for rotating can comprise a torsion spring and a cam mechanismfor controlling the rotation position, and/or a prime mover that ismechanically, electromechanically, or hydraulically driven.

The device optionally can include a growth factor or other growthstimulating agent for release in an effective amount to enhance growthof the blood vessel. Such agents may be impregnated into the materialsof construction forming the device or can be in the form of a coating ora reservoir device attached to the stretching device.

Also provided is an apparatus for extending a donor blood vessel of ahuman or animal in vitro. The apparatus includes a chamber containing aquantity of tissue culture growth medium; an inlet cannula extendingthrough a first orifice in the chamber, the inlet cannula having a firstend outside of the chamber and a second end positioned inside thechamber; an outlet cannula extending through a second orifice in thechamber, the outlet cannula having a first end outside of the chamberand a second end positioned inside the chamber; and a means, such as alinear motor, for moving the inlet cannula, the outlet cannula, or both,to axially stretch a donor blood vessel secured between the inletcannula and the outlet cannula in a submerged position in the tissueculture growth medium. In operation, a donor blood vessel is secured byhaving a first end of the vessel secured to the second end of the inletcannula and a second end of the vessel secured to the second end of theoutlet cannula, thereby forming a conduit through the blood vessel andbetween the first end of the inlet cannula and the first end of theoutlet cannula. Preferably, tissue culture growth medium flows throughthis conduit.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of one embodiment of the device for vesseldistension.

FIG. 2 is a plan view of a second preferred embodiment of the device forvessel distension.

FIG. 3 is a side elevational view of the distension device shownattached to a donor blood vessel.

FIGS. 4A and 4B are illustrations of a normal and stretched bloodvessel.

FIGS. 5A-C are front (5A), plan (5B), and side (5C) views of oneembodiment of the device for vessel distension using fixed points ofvessel attachment.

FIGS. 6A-C are diagrams showing vessel distension using a preferredembodiment of the device having points of vessel attachment that arefixed relative to one another.

FIGS. 7A-C are front (7A), plan (7B), and side (7C) views of oneembodiment of a device for both rectilinear and curvilinear vesseldistension.

FIGS. 8A-B are diagrams showing vessel distension using one embodimentof the device for both rectilinear and curvilinear vessel distension.

FIG. 9 illustrates a passive power source adaptable to powering thestretching device shown in FIG. 1.

FIG. 10 illustrates an organ culture or bioreactor system modified toallow axial extension of a blood vessel contained therein to inducegrowth.

FIGS. 11A-E are plan views of a preferred embodiment of a deviceemploying a pair of rotatable elements that provide both rectilinear andcurvilinear vessel distension.

FIGS. 12A-F are plan views (FIGS. 12A-B, 12D-F) and a side view (FIG.12C) of another preferred embodiment of a device employing a pair ofrotatable elements which provide both rectilinear and curvilinear vesseldistension.

FIGS. 13A-E are plan views (FIGS. 13A-D) and a side view (FIG. 13E) ofanother preferred embodiment of a device employing a pair of rotatableelements which provide both rectilinear and curvilinear vesseldistension.

FIG. 14 is a side view of a variation of a preferred device, wherein therotatable element includes multiple grooves for guiding a blood vesselduring the rotating and stretching process.

DETAILED DESCRIPTION OF THE INVENTION

It is known that smooth muscle cells, which dominate the media, themajor load bearing layer of the arterial wall, proliferate and increasetheir production of extracellular matrix in response to mechanicalstimulation. It was discovered that this knowledge could beadvantageously applied to create an autologous graft of appropriatediameter for coronary bypass or other vascular graft application using adistension device to stimulate angiogenesis. While an autologous graftis preferred, the devices and methods described herein also can beapplied to an artery from another human or other animal, includingtransgenic animals genetically engineered to have tissues that will notbe rejected by humans. The distension device can be adapted to operatein vivo or in vitro.

The devices and methods described herein can used to make allogeneic andxenogeneic vascular grafts, as well as the more preferred autogeneicvascular grafts.

Distension Device

The distension device secures the donor blood vessel at different pointson the vessel and then distends or stretches the vessel between thosepoints to form an elongated portion. The elongated portion can then beexcised for use as a vascular graft. Stretching can be continuous,cyclical, or intermittent, and can occur rectilinearly, curvilinearly,or in a combination thereof. The stretching can occur between vesselattachment points that are movable relative to one other or in fixedpositions relative to one other.

I. Movable Attachment Positions

The device typically includes a stretching mechanism that can beattached by means such as straps or sutures to the donor blood vessel, ameans for operating the stretching mechanism to cause the vessel todistend (i.e. extend), and a controller for controlling the operatingmeans.

A. Stretching Mechanism

In a preferred embodiment, the distension device stretching mechanismincludes a pair of opposed straps or loops that are fixedly attached tothe donor blood vessel such as by sutures. The opposed straps aredisplaced away from each other over a period of time so that the donorvessel elongates as the straps are displaced. After a period of time,such as when the straps are displaced a pre-determined distance, thesection of vessel and the device are removed and the ends of the donorvessel are sutured together if needed.

The device straps should be made out of a biocompatible material such asa synthetic or natural polymer or metal. The straps must be able to beattached to the vessel, for example, using sutures, staples, oradhesion. Examples of suitable material for the straps arepolytetrafluoroethylene (PTFE), polyester (e.g., DACRON™), nylon (e.g.,DELRIN™), polysulfone, polypropylene, and polyethylene. The strapmaterial preferably is doped to render it radio opaque, so that thestretching process can be monitored using x-ray techniques. The strapscan be wrapped in a material that is then attached to the vessel, orthey can include perforations or holes to accommodate suturing to thevessel. The straps preferably have a flex strength to support thedistending force applied on the stretching mechanism.

The device includes a means to displace the straps away from each otherand stretch the vessel. This displacement can be accomplished by any ofa variety of techniques. For example, the device can include rodsattached to the straps that can be moved to push or pull on the strapsto slowly displace the straps from each other. The rods can be moved,for example, by mechanical or hydraulic means.

B. Operating Means

The device includes means to operate the stretching mechanism,preferably including a prime mover and electronic drivers for the primemover, both of which are preferably implanted. The prime mover can be anelectromechanical (active) device, such as a linear-motor that operatesthe stretching mechanism to push and/or pull the straps away from eachother. A rotary motor could also be used to generate the required linearmotion, using techniques known in the art. Alternatively, the primemover can operate hydraulically. An active device generally requiresinput over time. The prime mover also can be a passive device such as aspring or a combination of a spring and a damper, where storedmechanical energy is used to push and/or pull the straps away from eachother.

Linear or rotary piezo micro-motor devices (actuators) deliver smallstep sizes, small forces, have relatively simple control electronics andinherent force overload protection. Suitable devices are available froma number of vendors, including Micro Pulse Systems, Inc. Parameters ofthe operating means include the force applied by the stretchingmechanism, the rate and direction of movement of the stretchingmechanism, the length of time that the stretching mechanism is operated,and the type of stretching applied (e.g., continuous, cyclical, orintermittent).

C. Controller

The controller controls the operating means. In the in vivo distensionembodiments, the controller can include a microprocessor that isimplanted and that can be activated, programmed, or reprogrammed by anexternally applied magnetic or electromagnetic field. The controlleralso can be activated, programmed, or reprogrammed externally usingwires that pass through the skin, or by wireless means for transmittingpower or data known in the art wherein wires need not pass through theskin.

One embodiment of the device is shown in FIG. 1. Proximal locking strap10 and distal locking strap 12 are of adjustable length appropriate fora secure fit around the donor blood vessel to be distended. Bloodvessels range from about 0.2 to 2 cm in diameter. The locking straps 10,12, include a lace 14, 16, respectively, of a biocompatible material,such as DACRON™, that can be secured to the donor vessel, such as bysuturing, stapling, or using an adhesive agent. In a preferredembodiment, the laces are designed similarly to the sewing rings of astandard artificial heart valve. Alternatively, a layer of a material,such as a fabric or film, can be attached to the strap so that thevessel can be sutured, stapled, or adhered to the material to hold thestrap to the vessel. In another embodiment, the strap includesperforations, holes, or other structural features amenable to suturingor stapling, so that the vessel can be sutured or stapled directly tothe strap. The locking straps each have a head 11, 13 with an internalaperture. Preferably, the straps 10, 12 include a plurality of teeth(not shown) that, when the free end of the lace 14, 16 is insertedthrough the aperture of the head of the strap, it engages the head andprevents the free end of the lace from becoming disengaged, in a mannersimilar to that of standard pull-ties. Alternatively, the head of thestrap can engage the strap if the lace 14, 16 does not cover the entirestrap or if the strap includes securing holes or perforations asdescribed above. The straps optionally may be impregnated or coated withone or more growth stimulating agents (e.g., growth factors) that can bereleased in an effective amount to promote vessel tissue growth duringthe stretching procedure.

Sliding bearings 18, 20, on straps 10, 12, respectively, and stops 22and 24, respectively, can be either attached to or integrally formed(during manufacture) with the straps or laces as shown. The bearings andstops are preferably made of the same material as the straps, althoughother biocompatible materials can be used.

A first push/pull rod 26 is fixedly attached to proximal tie strap 10 atstop 22. A second push/pull rod 28 is fixedly attached to distal tiestrap 12 at stop 24. The two push/pull rods are preferably initially notfitted to the locking straps but are easily assembled on the device invivo after the locking straps are secured around the vessel and suturedor otherwise fixed in place. The push/pull rods slide through thebearings 18, 20 and engage the stops 22, 24. The proximal locking strap10 including the lace 14, sliding bearing 18, stop 22, and the fixedlyattached rod 26 form a first integrated stretch unit 30. The distallocking strap 12 including the lace 16, sliding bearing 20, stop 24, andthe fixedly attached rod 28 form a second integrated stretch unit 32.Push/pull rods 26, 28 are preferably made of a rigid material such asstainless steel, titanium or a biocompatible, rigid plastic.

A wire (or cable) 36, preferably stainless steel or titanium, is fixedlyattached to first push/pull rod 26 at 38 and passes freely through ahole 40 in push/pull rod 28. The wire 36 then passes freely through thesheath 44 into the prime mover housing 46. The prime mover shown is apiezo-actuator or other linear motor. Those skilled in the art willrecognize that several suitable means for pulling the wire or cable areknown. For example, the wire or cable can be pulled by a hydrauliccylinder or actuator powered by an implanted pump or by transcutaneousinjection of a fluid, such as saline. The wire or cable also could bewound on a rotating reel or attached to a lead screw configured toproduce linear motion, wherein either is powered by electric orhydraulic rotary actuators. FIGS. 1 and 2 show two opposingpiezo-actuators 50 contained in the housing 46 which can be activated toprovide micron-sized step advancement of the driven element 52. Wire 36is attached to driven element 52 by a hook 54 or other means so thatwire 36 is advanced along with driven element 52. Micro Pulse Systems,Inc. makes micro-actuators that are suitable for the device disclosedherein.

As the actuator 48 pulls the wire 36, the first integrated stretch unit30 is pushed/pulled towards the actuator 48, in the direction of arrow53. The locking straps are thus displaced away from each other.

The device preferably includes an external driver and controller, whichare not shown in the Figures. In a preferred embodiment, the wire can beactivated from outside the body once the wire is passed through theskin. Mechanisms outside the body are easier to design andtranscutaneous catheters and similar conduits are highly developed.

A particularly simple passive device for producing the linear motionneeded to pull the wire 36 is illustrated in FIG. 9. The device 180includes a cylinder 182 having a first orifice 184 at one end 181 and asecond orifice 186 at the other end 183, and containing a movable piston188, a compression spring 190, and working fluid 192. Adjacent the oneend 181 is an extension 185 of the cylinder 182, which contains anabsorbent material 194 and includes a vent hole 196. The sheath 44 ofwire 36 enters the cylinder through second orifice 186, and the wire 36is attached to the piston 188 at its center 198. The spring 190, whichtypically is made of stainless steel, titanium or titanium alloy,particularly nickel-titanium, is in compression and pushes piston 188toward first orifice 184, thereby forcing the fluid 192, typically abiocompatible saline solution, through first orifice 184, where it isabsorbed by the absorbent material 194. Representative examples ofabsorbent materials include synthetic hydrophilic substances, such ascertain polymers, or natural materials, such as cellulose. Air or othergas in the interstices of the highly absorbent material 194 that isdisplaced by the fluid 192 exits from the piston through vent 196. Itcan be seen that the piston movement provides a continuous driving forceand linear motion to the wire or cable 36 in the embodiment shown inFIG. 1. The first orifice 184 can be of a fixed size or a variable sizeto control the movement of the piston 188. For example, orifices made ofpiezoelectric or magnetostrictive materials can be made to selectivelyvary in size by the application of an appropriate electric or magneticfield. The spring 190 can have a linear, nonlinear or constant forcedeflection characteristic and may consist of multiple springs actingtogether and designed to produce the required stretching force andmotion profile. Those skilled in the art will recognize that this devicecan be adapted to either push or pull on the cable or wire, depending onthe arrangement of the elements.

FIG. 2 illustrates a second embodiment 70 of a device for vesseldistension. The hydraulic embodiment uses two miniature, double-actinghydraulic cylinders 72, for example made of stainless steel, titanium orpolymer, through which hydraulic force is exerted to stretch the bloodvessel by pushing on straps 10. Double acting hydraulic cylinders 72 areconnected by a hydraulic line 74 into which fluid flows from the housing76 which comprise a reservoir of a fluid 77 such as saline. Pressure isgenerated by a piston 78 driven by threaded rod 80, positioned on a rodsupport 81, pushing the saline from the reservoir out at 83.Alternatively, pressure may also be generated by means external to thebody using a catheter through the skin or by injection into animplanted, subcutaneous port. Such ports are commonly available. Thethreaded rod 80 is driven using torque generated by frictionalengagement with piezo-actuators 82 or by a miniature permanent magnet orother suitable motor. Micro Pulse Systems Inc. supplies piezo-actuatorssuitable for use in the device. Driver electronics and a power sourceare indicated by 84. Note that while FIG. 2 shows a hydraulic mechanismwherein only strap 10 is moved, the hydraulic system may be readilyadapted by one of skill in the art to exert force on both strap 10 andstrap 12.

Alternatively, one skilled in the art could adapt the spring drivenpiston system illustrated in FIG. 9 to provide hydraulic power to theembodiment illustrated in FIG. 2.

The mechanical or hydraulic stretching mechanism works to move thestraps apart slowly over a period of up to several weeks. In oneembodiment, the passive driver element illustrated in FIG. 9 may be usedto provide a pre-determined stretch over time. In another embodiment,the driver may be pre-programmed to operate autonomously, or the drivermay be programmed (or reprogrammed) following implantation bytranscutaneous electromagnetic means, based, for example, on x-ray dataor other indications of how the process is proceeding. The driver may besimply turned on or off, or may be programmed or reprogrammed by amagnetic field sensing device such as a reed switch (relay) or by otherelectronic devices or circuits responsive to magnetic or electromagneticfields. The field is generated by using the external driver control toperiodically activate an external source positioned to activate theelectronic driver circuit. The external driver control may bepre-programmed to provide a stretch of several centimeters over aboutone month. Alternatively, cyclic stretching of increasing peak and meanamplitude may be used. Using piezo actuators, activating the driver canproduce incremental movements of the mechanical or hydraulic stretchingmechanism as small as a few microns. The prime mover is designed to beforce limited to preclude overstretching the vessel. Force limitation isinherent if the piezoelectric actuators are used in either embodimentand, in the case of permanent magnetic motors, can be designed into theelectronic driver circuit.

II. Fixed Attachment Positions

In stretching an artery to stimulate angiogenesis, the blood vesselportion that is beyond the region where the stretching apparatus isattached will be relaxed from its normal stretched state and couldpossibly be relaxed to the point where it is put in compression, asillustrated in the FIGS. 4A and 4B. FIG. 4A illustrates a blood vesselas it is normally stretched in vivo, and FIG. 4B illustrates how astretching device having points of contact (X) between vessel sections Aand B and between A and C. The stretching device elongates section Awhile relaxing sections B and C. The consequences of this are unknown,but can be avoided if the blood vessel is stretched between two fixedpoints, as described herein.

One embodiment of the fixed-point device is shown in FIGS. 5A-C. Thedevice 90 includes two semicircular or similarly shaped thin, yet rigid,plates 92 made of or completely covered by a biocompatible material,such as stainless steel, titanium, titanium alloy, fiber composite, orpolymer. The plates are separated and connected so as to remain parallelby a flat rectangular strip of similar material 94. The ends of thestrip 96 are perforated or otherwise formed to accept surgical suturesor other means (e.g., adhesive) known in the art to secure a bloodvessel to the strip at its ends. The ends 96 are also flexible andeasily bent, but without breaking, about axis 98 shown. The device canbe formed from a single appropriately shaped thin plate. The areabetween the plates contains at least one inflatable balloon 100, whichmay be formed from silicone, rubber, elastomeric polymers, or any otherhighly deformable biocompatible material. As the balloon 100 isinflated, it fills the space between the two thin plates 92 withoutsignificantly changing the spacing between the two plates 92, since theplates 92 and strip 94 are sufficiently rigid to ensure this. Inflationof the balloon 100 can be accomplished using at least one access port102, through which a fluid, such as saline, is injected, for example,through a needle or catheter connected to a syringe or similarlyfunctioning device. The inflation process can occur through the skin.The balloon is designed and attached to the strip in such a manner that,at full inflation, it assumes more or less the shape of the spacebetween the two plates confining it.

An alternative stretching mechanism is provided by hydrophilic orchemically reactive synthetic substances (e.g., various polymers) orother natural materials (e.g., cellulose) known to significantly expandtheir dry volume when activated as by exposure to fluid or possiblyother stimuli (e.g., heat, radiation or various chemical agents). Suchmaterials are available in foamed, fiber or other forms, any of whichmay be adapted by one of skill in the art to effect the ballooninflation described herein. One or more of these materials can be placedinside the balloon and expanded by the controlled addition of a fluid orchemical agent, such as by injection into the balloon, which causes thematerials to expand, inflating the balloon, in much the same way assimply pumping saline or another fluid into the balloon as describedabove. The material could also be otherwise encapsulated or separatedfrom the stimuli to control its means and rate of activation. Forexample, expandable material could be provided with a degradable coatingor other timed-release mechanism, and such mechanisms can be readilyadapted from those used in controlled drug delivery. Alternatively, theballoon can be omitted, and the hydrophilic or other volume expandingmaterial can simply be placed between the two plates in such a mannerthat exposure to body fluids or another appropriate stimulus causes thematerial to expand and fill the area between plates.

III. Combination Fixed/Movable Attachment Positions

Other embodiments combine rectilinear and curvilinear stretching. Onesuch embodiment is a slightly modified version of device 90 (shown inFIGS. 5A-C) and is illustrated in FIGS. 7A-C. The device 150 includesstrip 152, that is formed much like strip 94, except that it is formedin a slightly curved or angled configuration and includes at least one,and preferably several, plates (or tabs) 154, positioned at or near thelong edge of the strip 152 so as to form a channel 156. Strip 152 hasflexible ends 158 for attachment to the blood vessel. A blood vessel isplaced in channel 156 and attached to the strip 152, like described forstrip 94, wherein plates 154 serve to hold the blood vessel in place.The space between the plates contains one or more (three are shown)inflatable balloons 160, which are like balloon 100 described above.Inflation of the balloon(s) can be accomplished using at least oneaccess port 162, also as described above.

Method for Distending a Blood Vessel

The distension device can be adapted to operate in vivo or in vitro,that is to distend a portion of a blood vessel in vivo or following itsexcision from the body and subsequent placement in a medium for cellgrowth. As used herein, the phrase “medium for cell growth” includes anyin vitro system for facilitating cell division, extra-cellular matrixformation, and growth of vessel tissue. For example, the distensiondevice can be attached to an excised portion of donor vessel andsubmerged in a medium for cell growth in a temperature-controlledcontainer. As described in Example 1, it has been shown that distensionin an organ culture (e.g., a bioreactor) significantly stimulates celldivision, and can be simple to control. See, for example, U.S. Pat. No.5,899,936 to Goldstein; U.S. Pat. No. 5,879,875, to Wiggins, et al.; andU.S. Pat. No. 5,888,720 to Mitrani, which describe techniques for organand tissue culture which can be adapted to the methods described herein.

I. Operating the Movable Positions Device

The method for distending a donor blood vessel can include attaching astretching mechanism to the donor vessel and operating the stretchingmechanism to stretch the donor vessel. In one embodiment, the methodinvolves using a device wherein a pair of straps are fixedly attached tothe donor vessel and moved away from one another so that the portion ofthe vessel between the straps is distended. The distended portion canthen be excised and used as a graft. Grafts for coronary by-pass surgeryare typically between about 10 cm and 15 cm in length, whereas graftsfor by-pass in the peripheral circulation are typically about 25 cm ormore in length. Those of skill in the art can readily optimize the rateof vessel distension. Distension rates can be linear or nonlinear, andmay average, for example, between about 5 and 10 mm/day.

One embodiment of the method is illustrated in FIG. 3, wherein a device(e.g., the one shown in FIG. 1) is attached to a donor blood vessel 60.The device can be assembled before or at the time of implantation.Straps 10, 12 are engaged to encircle the donor vessel and are thensutured in place. Push/pull rods 30, 32 are attached to the straps. Wire36, and the housing assembly shaft 44, and housing 46 (containing theactuator) are attached to the device. Preferably, the active prime moveris implanted complete with its drive circuit and a minimal power source.Alternatively, a passive device, such as described above, can be used.As either device is operated, the section of vessel 60 between thestraps 10, 12, indicated by 62, stretches.

II. Operating the Fixed Positions Device

The device using fixed attachment positions is preferably operated asshown in FIGS. 6A-C, which show a cross-sectional view (a—a) of thedevice in FIGS. 5A-C, at increasing degrees of vessel distentionoccurring with increasing inflation/expansion of the balloon/expandingmaterial. In operation, the target blood vessel 93 is placed between thetwo plates 92, resting on the uninflated balloon 100 (or unexpandedmaterial) and secured to the flexible ends 96 of the strip 94, forexample by sutures or other suitable means (FIG. 6A). As the balloon isinflated (or the material expanded), the blood vessel 93 is stretched(FIG. 6B), between the two fixed ends 96 and continues to stretch as thespace between the two plates is filled (FIG. 6C), without thepossibility of reducing the tension in or compressing the blood vessel93 not between the points of attachment.

III. Operating the Combination Fixed/Movable Positions Device

The device using the combination of fixed and movable attachmentpositions is preferably operated as shown in FIGS. 8A-B. FIG. 8A shows ablood vessel attached to the device before application of the bendingforce (i.e. before distension). FIG. 8B shows the device and bloodvessel following application of the bending force, wherein strip end Ais drawn towards strip end B. The device can be, for example, device 150described above.

In operation, the target blood vessel 153 is first placed in the channelformed by plates 154, resting on the uninflated balloon 160 and securedto the flexible ends 158 of the strip 152, for example by sutures orother suitable means. The ends 158 of the strip 152 are then drawntowards each other by mechanical or other forces to cause strip 152 tobend or flex, thereby stretching the blood vessel 153. The ends can bedrawn towards one another by any suitable means, including a mechanicalor magnetic force, or by a differential expansion effect, for examplewhere the strip consists of laminates of materials that contract orexpand differently from one another when exposed to a stimulus, such asheat (thermal expansion) or water (e.g., top layer of strip hydrophilicwhile bottom layer hydrophobic). The mechanical means can include, forexample, the linear or rotary piezo micro-motor devices describedherein. As the strip 152 is bent, distance C increases and distance ABdecreases, causing the section beyond either A or B to be stretched in arectilinear manner.

Additionally, as balloon 160 is inflated (or the material expanded), theblood vessel is stretched between the two ends 158 and continues tostretch as the space in the channel defined by plates 154 is filled.Thus, the section of blood vessel between ends A and B is stretched in acurvilinear manner. The two modes of stretching can occursimultaneously, one after another in either order, or any combinationthereof.

IV. In Vitro Operation

Currently, a short segment of blood vessel can be salvaged duringconventional bypass surgery and an in vitro organ culture or bioreactorsystem can be used to grow sufficient graft tissue for a second surgery.Such surgeries represent about 30% of all bypass operations. The methodsand devices described herein can be adapted to work with such surgeries,to increase the length of graft material and/or to reduce the requiredlength of the salvaged segment. Stretched blood vessels can beeffectively preserved for bypass surgery, for example, using knowncryogenic or freeze-drying techniques.

FIG. 10 illustrates an organ culture or bioreactor system 200 modifiedto accommodate the need to stretch a blood vessel to induce growth. Adonor blood vessel 202 is connected at its two ends to first and secondcannulas 208 and 210 so that it is continuously immersed in a suitabletissue culture medium 206 at physiological temperature. A representativeexample of a tissue culture medium consists of DMEM (Sigma D1152),sodium bicarbonate (3.7 g/L, Sigma), L-glutamine (2 mM, Sigma),antibiotic-antimycotic solution (10 ml/L, Gibco), calf serum (CS 10%,Integren) and, possibly, Dextran (5% by weight, MW 282,000 Sigma). Themedium 206 is contained a liquid-tight chamber 204, having gas inletaperture 212 and gas outlet aperture 214, to permit gases, such as amixture including oxygen and carbon dioxide, to enter the chamber 204,exchange gases with the medium 206, and then exit the chamber 204. Thechamber 204 may also include one or more openings (not shown) to permitchanging or replenishing of the medium 206. Second cannula 210 isgenerally fixed and passes into the chamber 204 through seal 216,whereas first cannula 208 passes through a sliding seal 218 and can movelinearly to effectively stretch or relax the blood vessel 201. Thelinear motion of the cannula or the force exerted on the blood vesselcan be controlled by a linear motor or by means such as describedherein. Tissue culture medium, at physiological temperature and pressure(including pulsatility), preferably is continuously introduced intocannula inlet 220, flows through blood vessel 202, and then exits fromcannula outlet 222. This internal medium also should be exposed tocarbon dioxide and oxygen gases so that gas exchange can occur.

Application of the Distension Devices and Methods

The present devices and methods are useful for forming a vascular graftby axially stretching (i.e. distending or extending) a donor bloodvessel to stimulate growth. This stretching can performed in vivo or invitro.

The devices and methods can be sized to stretch blood vessels ofessentially any size and located in or excised from a variety of sitesin the body of the patient or donor or animal. Preferred blood vesselsinclude, but are not limited to, the internal mammary arteries, thegastroepipolic artery, the gastric artery, the radial artery, thefemoral artery, and the splenic artery. Other arteries and veins mayalso be suitable blood vessels for use with the methods and devices.

In a preferred embodiment of the in vivo distension method, the deviceis implanted, for example using endoscopic techniques, in the patientand vessel distension effected over a period of time. Then the site ofimplantation is reexposed, all or a portion of the donor blood vesselsection (e.g., vessel segment 62 in FIG. 3) is removed and the device isexplanted. The ends of the donor vessel can then be sutured end to endto repair the donor vessel, as is commonly done in vascular repairwithout complication. Some blood vessels used for coronary bypasssurgery, such as the gastroepipolic and radial arteries, can be removedwith minimal morbidity such that repair is unnecessary. The removedblood vessel section is then ready for use as a graft in a patient inneed thereof, who preferably is the same patient supplying the donorvessel.

In a preferred embodiment of the in vitro distension method, a portionof donor blood vessel (e.g. shorter than that needed for a graft) issurgically excised from the patient in need of the graft, and then thevessel portion is stretched over a period of time in vitro in a mediumfor cell growth, for example, as in a bioreactor. All or a portion ofthe distended vessel is then ready for use as a graft in the patient.Where the donor is the recipient of the graft, the result using eitherapproach advantageously is a totally autologous, living vascular graft.

Preferred Embodiments

In a preferred embodiment of the device, the stretching mechanism is notactually attached to the blood vessel and is therefore easier to use, asno suturing of the device to the vessel is required. The device alsopreferably is enclosed so that the possibility of tissue adhesions tosoft tissue and/or infiltration by body fluids—potential problems withessentially any implanted device—is minimized. The device alsopreferably includes a growth stimulating agent, such as a growth factor,to stimulate blood vessel tissue growth. For in vivo applications, thedevice also preferably is sized and shaped to facilitate minimallyinvasive implantation, such as by endoscopic insertion.

Preferably, the device comprises a stretching mechanism which includes(i) a stabilization rod, (ii) a pair of rotatable elements, wherein eachrotatable element is rotatably attached to the stabilization rod and hasa channel substantially perpendicular to the axis of rotation, and (iii)a means for rotating each rotatable element to axially distend a bloodvessel positioned in the channels of the rotatable elements. As usedherein, the term “substantially perpendicular” includes angles between 0and 20°, preferably between about 0 and 10°, and more preferably between0 and 5°.

One variation of such an embodiment is shown in FIGS. 11A-E as device250. The device 250 includes a stabilization rod 252 and two rotatableelements 254 a and 254 b, which are rotatably attached to thestabilization rod 252. Rotatable elements 254 a and 254 b each include apair of arms 256 capable of bending or flexing between a straight and acurved configuration, as shown by comparing FIGS. 11A and 11B. FIG. 11Aillustrates the device 250 in a collapsed form, which provides a profilethat is well suited to endoscopic insertion. FIG. 11B shows the device250 in an expanded form as it would appear after insertion into the bodybut prior to use in stretching a blood vessel. The elements of thisembodiment can be fabricated using suitable materials and methods toaccomplish the transformation of shape shown. The arms 256 preferablycan be maintained in a collapsed, straight profile (FIG. 11A) with oneor more releasable fasteners (not shown) securing the arms to oneanother or to the stabilization rod, so that the device 250 can beeasily implanted. Representative examples of releasable fastenersinclude thin breakable connections, bonds, or welds, as well as screws,clamps, and hooks. A removable sleeve that snugly fits around the armsand stabilization rod may also serve as a fastener to hold the arms in acollapsed profile. Such a sleeve could simply be slid off of thestabilization rod following insertion to release the arms. The shapechange of the arms 256 is preferably due to a spring action inherent inthe material of construction of the arms 256, such that, upon release(e.g., upon breaking of the connection, bond, or weld), the arms willtransform from the straight configuration (FIG. 11A) to the curvedconfiguration (FIG. 11B). Such a transformation can occur as a result ofthe elastic restorative forces normally exhibited in most metals andpolymeric materials, forces that could be made, by one skilled in theart, to straighten a curved element formed from these materials.Nickel-titanium alloys, which exhibit super-elastic and shape-memoryeffects, are particularly suitable. Shape memory nickel-titanium alloysand certain polymeric materials can be fabricated to change shape fromstraight to curved as the device warms to body temperature after it isinserted. Examples of shape memory polymers are described, for example,in PCT WO 99/42528 and U.S. Pat. No. 6,160,084, which are incorporatedherein. Methods for forming the elements of the device are well known tothose skilled in the art.

FIGS. 11B-11E illustrate use of the device 250 with a blood vessel 260(represented as a broken line). These figures also illustrate therotational movement of the rotatable elements 254 a and 254 b. First,the blood vessel 260 should be threaded into element channels 258 a and258 b of rotatable elements 254 a and 254 b, respectively, and then therotatable elements 254 a and 254 b are rotated to cause the vessel 260to stretch, in a combination of rectilinear and curvilinear stretching.The vessel 260 is frictionally engaged with the rotatable elements 254and arms 256, and need not be sutured or otherwise attached to thedevice 250. To better grip the blood vessel 260, the arms 256 can have asuitably curved cross section or groove similar to the grooves describedin the embodiment shown in FIG. 12B. FIGS. 11D and 11E show successiverotation of rotatable elements 254 a and 254 b, as well as theassociated lengthening of blood vessel 260.

Another variation of a preferred embodiment is shown in FIGS. 12A-F asdevice 270. The device 270 includes a stabilization rod 272 and tworotatable elements 274 a and 274 b, which are rotatably attached to thestabilization rod 272. The rotatable elements 274 a and 274 b each havea pair of rounded lobes extending from a central base, thereby providinga shape with a smooth, rounded profile to permit insertion with anendoscope, while not requiring the device to have a collapsedconfiguration as in device 250. FIG. 12A illustrates the device 270 inits insertion profile. FIG. 12B shows the device 270 in an expanded formas it would appear after insertion into the body, with rotatableelements 274 a and 274 b rotated slightly to align channels 276 a and276 b with the stabilization rod 272, rendering the device 270 ready forthreading with a blood vessel 280 (represented as a broken line). Theelements of this embodiment can be fabricated using suitably rigidmaterials and known fabrication methods. Materials such as stainlesssteels, titanium, titanium alloys or biocompatible polymers aresuitable. Methods for forming the elements of the device are well knownto those skilled in the art. FIG. 12C illustrates a side view ofrotatable element 274 a along line d—d in FIG. 12B. Rotatable elements274 a/b include grooves 278 at its periphery, as shown in FIG. 12C, tosupport and guide the blood vessel 280, keeping it from slipping off ofthe rotatable elements 274 a/b as the rotatable elements 274 a/b rotate.Such grooves are optional.

FIGS. 12B and 12D-12F illustrate use of the device 270 with a bloodvessel 280. These figures also illustrate the rotational movement of therotatable elements 274 a and 274 b. After blood vessel 280 is threadedinto element channels 276 a and 276 b of rotatable elements 274 a and274 b, respectively, the rotatable elements 274 a and 274 b are rotatedto cause the vessel 280 to stretch. More rotation will yield more vesselstretching, and thus a greater length of vessel graft material provided.

Yet another variation of a preferred embodiment is shown in FIGS. 13A-Eas device 290. The device 290 includes a stabilization rod 292 and tworotatable elements 294 a and 294 b, which are rotatably attached to thestabilization rod 292. The rotatable elements 294 a and 294 b are, likeelements 274, shaped to have a smooth, rounded profile to permitinsertion with an endoscope; however, elements 294 are in a shape thattypically should be somewhat simpler to manufacture. FIG. 13Aillustrates device 290 in is insertion profile. FIG. 13B shows thedevice 290 in an expanded form as it would appear after insertion intothe body, with rotatable elements 294 a and 294 b rotated slightly toalign channels 296 a and 296 b with the stabilization rod 292, renderingthe device 290 ready for threading with a blood vessel 300 (representedas a broken line). The elements of this embodiment also can befabricated using suitably rigid materials and known fabrication methodssimilar to those described for the devices illustrated in FIGS. 11 and12. FIG. 13E illustrates a side view of rotatable element 294 a alongline e—e in FIG. 13B. Rotatable elements 294 a/b includes grooves 298 atits periphery, as shown in FIG. 13E, to support and guide the bloodvessel 300, keeping it from slipping off of the rotatable elements 294a/b as the rotatable elements 294 a/b rotate.

FIG. 14 shows a variation of a rotatable element 310, which is providedwith multiple grooves 312 for supporting and guiding a blood vessel. Ascan be seen, the grooves 312 are in a threaded arrangement to permitmultiple revolutions of the rotatable element 310, rendering a devicecapable of further increasing the length of blood vessel produced bystretch induced growth.

In all of these preferred embodiments and variations, the stabilizationrod preferably is a substantially rigid, elongated body or structure.The devices are designed so that their cross-sectional dimensionsfacilitate endoscopic implantation, preferably using available hardware.Standard trocars for endoscopic access range in size to 25 mm. Devicelength is influenced by choice of artery, length of graft produced, andother factors. The expected length is between about 4 cm and 20 cm.

While two rotatable elements are shown and preferred, the device alsocan work with one or three or more rotatable elements. Additionalrotatable elements can be added, by one skilled in the art, if needed toproduce a single, more complex, device capable of additionallengthening. When such additional lengthening is necessary, it can bemore easily achieved using multiple devices as described.

The rotational movement of the rotatable elements can be driven by awide variety of forces and driver means known in the art. For example,the means for rotating the rotatable elements can include a torsionspring and a cam mechanism for controlling the rotation position. Thespring and cam preferably are situated within the stabilization rod. Therotation also may be conducted using mechanical, electromechanical,hydraulic, or other means known for controllably rotating structuresrelative to a base structure, for example, by adapting one or more ofthe means described above. In a preferred embodiment having two rotatingelements, each rotates in opposite directions from one another.Additional (dynamic) stretching of a blood vessel can be achieved byvariable longitudinal placement of the elements from one another alongthe stabilization rod. For example, one of the rotatable elements can bea floating mechanism that can be moved along the stabilization rod awayfrom the other, fixed, rotatable element, thus providing additionalstretch to the blood vessel segment between the rotatable elements.

Additional means for producing the required rotational motion includedirectly driving the rotatable elements using suitably controlled rotarymicromotors. Common mechanical elements, such as racks and pinions, canbe combined to convert linear to rotary motion. Such mechanisms can bedriven by linear or geared rotary motors or by elastic stored energy,such as the energy stored in a tension or compression spring, or byhydraulic means or by some combination of these means. Activation of oneor both of the rotatable elements, either synchronously orasynchronously, continuously or intermittently, can be used as mostappropriate for a particular embodiment.

The methods and devices described herein optionally can include growthfactors or other growth stimulating agents (e.g., hormones) to furtherenhance blood vessel growth. For example, such growth stimulating agentscan be delivered to the blood vessel by impregnating the materialsforming the device or by providing a suitable coating or reservoirs inthe device that can contain and controllably release such agents duringthe extension process. Examples of growth factors include vascularendothelial growth factor (VEGF), endothelial cell growth factor (ECGF),basic fibroblast growth factor (bFGF), and platelet derived growthfactor (PDGF). Biocompatible polymeric materials for controlled releasethat are known in the art for drug delivery (see e.g., U.S. Pat. No.5,879,713 to Roth et al.) can be adapted for use with the devicesdescribed herein. The devices and methods also can be used incombination with external electric, magnetic, or electromagnetic fieldsapplied as a growth stimulus (see e.g., U.S. Pat. No. 4,846,181 toMiller).

The devices also can optionally include appropriate drugs (e.g.,therapeutic or prophylactic agents) impregnated into or coated tostructural components, for example to minimize infections, inflammatoryreactions, scar tissue formation, adhesion formation, and/or otheradverse tissue reactions. For example, where tissue growth is to beavoided, certain antifibrotic agents may be present, such as5-fluourouracil or mitomycin. The device may be more generally providedwith coatings that are antibiotic or anti-inflammatory.

The devices also can be enclosed in a suitable sheath to limit adhesionformation and/or infiltration by body fluids while implanted in vivo, orbe impregnated or coated with materials selected to reduce adhesionformation as known in the art. Examples of such coating materialsinclude, but are not limited to, parylene, polytetrafluoroethylene(e.g., TEFLON™) and chromium (e.g., ME-92™, Armoloy Corp.), which can beused to coat a variety of other metal and polymer substrates.

The devices and methods of use thereof described herein are furtherdescribed by the following non-limiting examples.

EXAMPLE 1 In Vivo Vessel Stretching to Stimulate Cell Division

Leung et al., Science 191:475-77 (1976) showed that cyclic stretchingstimulates synthesis of matrix components in arterial smooth musclecells in-vitro. Subsequent studies in arterial tissue have been limitedto the effects stretching on cells attached to a membrane in cellculture (see, for example, Birukov, et al., Molecular & CellularBiochem. 144:131-39 (1995); Costa, et al., FASEB J. 5:A1609-7191 (1991))or in a vascular graft construct (Kanda, et al., Cell Transplantation4(6):587-95 (1995)). No known studies, however, have analyzed the effectof stretch on cells in intact vessel walls. Therefore, a study was madeof porcine carotid arteries in an organ culture system developed byConklin (Conklin, B. Viability of Porcine Common Carotid Arteries in aNovel Organ Culture System MS Thesis, Georgia Institute of Technology,1997), in order to determine the effect of axial stretching on smoothmuscle cell division in an intact vessel. See also Han, H. C., Vito, R.P., Michael, K., Ku, D. N., “Axial Stretch Increases Cell Proliferationin Arteries in Organ Culture”, Advances in Bioengineering, ASME, BED48:63-64 (2000).

Left and right external carotid arteries were obtained at slaughter, onefor testing and the other serving as a control. Both vessels wereimmersed in cell culture media containing DMEM (Sigma D1152), sodiumbicarbonate (3.7 g/L, Sigma), L-glutamine (2 mM, Sigma),antibiotic-antimycotic solution (10 ml/L, Gibco), and calf serum (CS10%, Integren). The vessels were perfused with the same media with theaddition of Dextran (5% by weight, MW 282,000 Sigma). The test andcontrol specimen both were maintained at body temperature and subjectedto ulsatile flow in the physiological range. The control specimen wasrestored to and maintained at the in-vivo length, which corresponds to astretch ratio of 1.5, for the duration of the experiment. The testspecimen was stretched an additional 30% to a stretch ratio of 1.8 overthe first two and one-half days of the five day experiment.

Bromodeoxyuridine (“BRDU”) staining was used to compare the number ofcells that were dividing in the test and control specimens. On the fifthday, the specimens were pressure-fixed with formalin and histologicslides prepared for cell counting using light microscopy. The BRDU wasadded on day four and the test specimen showed that 6.8+/−2.8% of thecells were dividing, while only 3.08+/−2.9% of the cells were dividingin the control specimen. The results clearly suggest that axialstretching can be used to enhance cell division in blood vessels, andshould therefore be useful in the growing vessel segments for use increating blood vessel grafts.

Modifications and variations of the present invention will be obvious tothose of skill in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe following claims.

We claim:
 1. A device for axially extending a blood vessel of a human oranimal to induce growth of the blood vessel, comprising: a stretchingmechanism which comprises (i) a stabilization rod; and (ii) a pair ofrotatable elements, each rotatable element rotatably attached to thestabilization rod and having a channel substantially perpendicular tothe axis of rotation; and (iii) a means for rotating each rotatableelement, to axially extend a blood vessel positioned in the channels ofthe rotatable elements.
 2. The device of claim 1, further comprising acontroller for controlling the means for rotating.
 3. The device ofclaim 2, wherein the means for rotating comprises a torsion spring and acam mechanism for controlling the rotation position.
 4. The device ofclaim 1, wherein the means for rotating can rotate the rotatableelements in a continuous manner.
 5. The device of claim 1, wherein themeans for rotating can rotate the rotatable elements in an intermittentmanner.
 6. The device of claim 1, wherein the means for rotating canrotate the rotatable elements in a cyclical manner.
 7. The device ofclaim 1, wherein the rotatable elements each comprise a pair of armsextending from a central base, the arms being capable of bending orflexing between a straight configuration and a curved configuration. 8.The device of claim 7, wherein in the straight configuration the armsextend from the central base along a line substantially parallel to thestabilization rod.
 9. The device of claim 8, wherein the arms aremaintained in the straight configuration by one or more releasablefasteners securing the arms to one another or to the stabilization rod.10. The device of claim 9, wherein the arms have an inherent springaction and the relaxed state of the arms is a curved configuration, andwherein the arms will transform from the straight configuration to thecurved configuration upon release of the releasable fasteners.
 11. Thedevice of claim 10, wherein the arms comprise a shape memory material.12. The device of claim 11, wherein the shape memory material comprisesnickel-titanium or a shape memory polymer.
 13. The device of claim 1,wherein the rotatable elements each comprise a pair of rounded lobesextending from a central base, the channel extending between each pairof lobes.
 14. The device of claim 13, wherein the lobes comprise adisk-shaped portion having an outer edge surface distal the axis ofrotation of the rotatable element and a substantially flat upper surfacedistal the stabilization rod.
 15. The device of claim 14, wherein theouter edge surface comprises one or more grooves in which a blood vesselor portion thereof can be positioned.
 16. The device of claim 15,wherein the outer edge surface comprises a plurality of grooves arrangedto form a threading surface around the rotatable element.
 17. The deviceof claim 1, wherein the means for rotating comprises a primer mover thatis mechanically, electromechanically, or hydraulically driven.
 18. Thedevice of claim 1, wherein a first rotatable element is slidablymoveable along the length of the stabilization rod and away from asecond rotatable element to enhance vessel stretching therebetween. 19.The device of claim 1, further comprising a therapeutic or prophylacticagent.
 20. The device of claim 19, wherein the a therapeutic orprophylactic agent comprises a growth stimulating agent which can bereleased in an effective amount to enhance growth of the blood vessel.21. The device of claim 1, wherein all or a portion of the device isradioopaque.
 22. The device of claim 1, wherein the rotatable elementscan be positioned and/or are shaped to have a narrow profile such thatthe device is suitable for endoscopic insertion into a patient.
 23. Amethod for distending a blood vessel of a human or animal to induceblood vessel growth, using the device of claim 1, comprising the steps:threading a portion of a blood vessel into the channels of the pair ofrotatable elements; and rotating both rotatable elements to axiallystretch the blood vessel over a period of time effective to induce axialgrowth of the blood vessel.
 24. The method of claim 23, wherein thestretching occurs in vivo.
 25. The method of claim 23, wherein thestretching occurs in vitro in a medium for cell growth.
 26. The methodof claim 23, wherein the rotatable elements are rotated in a continuousmanner.
 27. The method of claim 23, wherein the rotatable elements arerotated in an intermittent manner.
 28. The method of claim 23, whereinthe blood vessel is selected from the group consisting of an internalmammary artery, a femoral artery, a gastroepipolic artery, a gastricartery, a radial artery, and a splenic artery.
 29. A method of forming avascular graft for a human or animal in need thereof, comprising:distending a donor blood vessel of a human or animal to induce bloodvessel growth, using the device of claim 1, comprising the steps:threading a portion of a blood vessel into the channels of the pair ofrotatable elements; and rotating both rotatable elements to axiallystretch the blood vessel over a period of time effective to induce axialgrowth of the blood vessel; and excising a portion of the distendeddonor vessel, said portion thereby providing a vascular graft.